Process for preparing esters of organic carboxylic acids



Patented Jan. 25, 19 49 s PATENT PROCESS FOR'PR-EPARING ESTERSEOFORGANIC GARBOXYLIC ACIDS RichardF. Phillips, Westfield; N. J., .assignorto Merck & Co.,,lnc., Bahway-,.N. J}, a corporation or New Jersey NoDrawing. Application July 13, 1946, Serial No. 683,429

4 Claims. 1

This invention relates to the preparation of esters of organiccarboxylic acids. More particularly, it is concerned with thepreparation of esters of N-acylamino acids, which are useful in thesynthesis of penicillin and of compounds possessing penicillin-likeactivity.

Regarded in certain of its broader aspects, the process in accordancewith the present invention comprises reacting an organic carboxylicacid, such as N-acylamino acids with analkyl sulfite in the presence ofthe corresponding alcohol and an acidic catalyst.

N-acyl glycines, which are useful as starting materials in accordancewith my invention can. be prepared by reacting glycine with an acylchloride. The general process and the compounds thereby secured aredisclosed and claimed in a copending application to my colleagues,Rogers, Koniuszy and Folkers, Serial No. 636,255, filed December 20,1945 which is now abandoned.

In accordance with the present invention, N-acyl glycine is refluxedwith approximately a molar equivalent of an alkyl sulfite in thepresence of the corresponding alcohol and an acid catalyst. The amountof alcohol and acid necessary for the reaction is small. Upon completionof the reaction, the excess acid is neutralized with potassiumcarbonate. Since only a small quantity of acid is used the reactionmixture is rapidly neutralized. The mixture is then filtered and theN-acyl glycine ester recovered from the filtrate by distillation. N-acylglycines prepared in this manner are obtained in high yields. Alkylsulfites such as dimethyl sulfite or any of the higher homologs, ethyl,propyl, etc., can be employed in this reaction.

The following examples set forth a method of carrying out the presentinvention, but it is to be understood that these examples are given byway of illustration and not of limitation.

Example 1 N-n-butyrylglycine was prepared by reacting butyryl chloridewith glycine. A mixture of 14.5 g. of N-n-butyrylglycine (0.1 mole), 12g. of dimethyl sulfite (0.11 mole), 11 g. of methanol and 0.5 cc. of a20% solution of hydrogen chloride in methanol was heated at refluxtemperature for 3 hours. The mixture was cooled and the excess acidneutralized with dry potassium carbonate until a drop of the solutionfailed to produce a blue color with Congo red paper. The mixture wasfiltered and the filtrate distilled under reduced pressure. 14.7 g. (92%of theory) of N-n-butyrylglycine methyl ester, which distilled 2 sharplyat 118 C. and 0.9 mm. pressure, was obtained.

Example 2 n-Caproylglycine was prepared by the reaction of 374 g.of-caproyl chloride with 228 g. of glycine. The crude n-caproylglycineobtained was treated with a mixture of 200 cc. of methanol, 169 g. ofdimethyl sulfite and '7 cc. of a 20% hydrochloric acid solution inmethanol at reflux temperature for 3 hours. The reaction mixture wascooled and the excess acid neutralized with dry potassium carbonateuntil a drop of the solution fails to produce a blue color with Congored paper. N-n-caproylglycine methyl ester, with a boiling point of 127to 130 C. at 0.25 mm. pressure, was obtained in a 86% yield (based oncaproylchloride).

Example 3 Iso-valerylglycine was prepared by reacting 330 g. of glycinewith 484 g. of iso-valerylchloride. A mixture of the iso-valerylglycineobtained, 440 cc. of methanol, 390 cc. of dimethylsulfite, and 20 cc. ofa 20% hydrochloric acid solution in methanol was heated at refluxtemperature for 4 hours. The reaction mixture was cooled and the excessacid neutralized with dry potassium carbonate until a drop of thesolutions failed to produce a blue color with Congo red paper.N-iso-valerylglycine methyl ester, with a boiling point of 108-110 C. at0.65 mm. pressure was obtained in a 79% yield (based onisovalerylchloride) Modifications may be made in carrying out thepresent invention without departing from the spirit and scope thereofand the invention is to be limited only by the appended claims.

I claim:

1. The process that comprises reacting an N-acylamino acid withapproximately a molar equivalent of a dialky1 sulfite in the presence ofthe corresponding alcohol and an acidic catalyst to form an N-acylaminoester.

2. The process that comprises reacting N-nbutyrylglycine withapproximately a molar equivalent of dimethyl sulfite in the presence ofmethanol and an acidic catalyst to form N-nbutyrylglycine methyl ester.

3. The process that comprises reacting N-isovalerylglycine withapproximately a molar equivalent of dimethyl sulfite in the presence ofmethanol and an acidic catalyst to form N-isovalerylglycine methylester.

4. The process that comprises reacting N-ncaproylglycine withapproximately a molar 4 equivalent of dimethyl sulfite in the presenceof OTHER REFERENCES methanm i an a catalyst mm Bondi et aL, Biochem.z.," v01. 23, (1910), caproylglycme met yl ester. pages 500 501 502 andKarrer et aL, "Helv. Chim. Acta., vol. 8, RICHARD PHILLIPS- 5 (1925),pages 208 and 209.

REFERENCES CITED pagzgaliigrg, Comptes Rendus, vol. 190, (1930), Thefollowing references are of record in the Voss et al. (I), LiebigsAnnallen, 485 (1935), file of this patent: 10 pages 265- 83.

Voss (et a1. (II), Ber. Deut. Chem, vol. 70, UNHED STATES PATENTS1,937), pages 388-392. Number Name Date Lassar-Cohn, Arbeitsmethoden furOrganisch- 1,365,050 Ellis Jan. 11, 1921 chemische Laboratorien, 4thed., special part 2,183,357 Ritchie et a1. Dec. 12, 1939 page 275.

